Characterization of an expanded large granular lymphocyte subset lacking natural killer activity present in renal allograft recipients

We have previously reported that, in long-term renal allograft recipients who receive chronic chemical immunosuppression and who are at risk for late chronic viral infections and virus associated tumors, the percentage of lymphocytes the phenotype of which is Leu-7+/Leu-11(-) (CD16) is markedly and significantly increased compared with that in normal controls. Since this population may lack natural killer (NK) activity and may explain the state of decreased host resistance, we carried out studies in 16 kidney transplant recipients on conventional immunosuppression and 10 age-matched normal controls to further define the phenotype, the morphology, and the NK cell activity of this particular subset. Using two-color flow cytometry analysis we found that the Leu-7+ cell subset comprises two essentially nonoverlapping subpopulations, depending on whether cells are coexpressing the NK cell marker Leu-11/CD16 (Leu-7+/Leu-11+ phenotype) or the pan-T cell marker Leu-4/CD3 (Leu-7+/Leu-4+ phenotype). We thus demonstrated that Leu-7+/Leu-11- cells do coexpress the Leu-4+/CD3 surface determinant. The percentage of Leu-7+/Leu-4+ (CD3) is significantly elevated in transplant recipients compared with that in normal controls (26 +/- 4% versus 8 +/- 2%, P less than 0.005). In contrast, the size of the Leu-7+/Leu-11+ cell subset is similar in both groups. Although in transplant recipients 70% of Leu-7+ cells coexpress Leu-4/CD3, only 43% do so in the control group. Cell sorter experiments isolated the Leu-7+/Leu-4+ cells and showed that morphologically these cells are typical large granular lymphocytes that cannot be distinguished from Leu-11+ NK cells. NK-sensitive K562 target cells showed no cytotoxicity. In contrast, Leu-7+/Leu-11+ cells exhibited high killing activity. Therefore, in long-term stable renal allograft recipients at increased risk of developing cancers and chronic viral infections, a subpopulation of non-NK large granular lymphocytes, the phenotype of which is Leu-7+/Leu-11-/Leu-4+, is abnormally expanded. This subset likely contributes to the diminished functional attributes of the chronic drug-induced immunodeficiency.